Even though neuroendocrine pathways have been systematically studied and defined as having regulatory properties of vasculature architecture related to hypertension; it has recently become evident that their effect is entirely dependent upon the CD4+ lymphocyte. Hypertension cannot be induced with angiotensin II or DOCA in CD4+ deficient mice and secondly hypertension can be adoptively transferred with CD4+ lymphocytes from hypertensive mice to naove mice. There are four subtypes of CD4+ lymphocytes; Th1, Th2, Th17, and Treg each of which have their own unique function, expressed cytokines, and effector proteins. Taken together, do the classic hypertensive neuroendocrine pathways affect balance and function of these CD4+ lymphocyte subsets? Secondly there are three major cell types in the arterial vasculature; endothelial, smooth muscle, and adventitial fibroblasts all of which are inter-connected by the vascular extracellular matrix. Therefore what is the target vascular cell and cellular function that is dependent upon by the CD4+ lymphocyte? Our over-all goal is to demonstrate that skewing of the CD4+ lymphocyte responses towards Th17 or Th1 and away from Treg by the neuroendocrine pathways may be responsible for the vascular extracellular matrix remodeling. This primary goal will focus further on select candidate Th17 and Th1 cytokines and vascular enzymes that form extracellular matrix crosslinking. We plan to compare three different rodent models of hypertension, namely; angiotensin II, DOCA, and L-NAME, with in vivo and ex vivo analysis of vascular stiffness, renal function, selected immune modulation of Th1, Th2, Th17, and Treg function, and molecular, histological, and mass spectrophotometric analysis of the concentration and composition of the vascular fibrillar collagen and elastin. The extracellular matrix compositional changes that we propose to associate with immune based hypertensive vascular stiffening is an increase in the level of lysyl oxidase mediated collagen and elastin crosslinking. In summary, we plan to demonstrate that early or pre-hypertensive states are due to a Th17/Th1 mediated alteration of the vascular extracellular matrix composition.